Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder characterized by the presence of senile plaques in various brain areas. AD plaques are insoluble protein aggregates mainly composed of a 4 kDa peptide known as beta-amyloid peptide (Abeta). Abeta is generated by proteolytic cleavage from a transmembrane glycoprotein termed beta-amyloid precursor protein (APP). The factors governing the production and deposition of Abeta, as well as the exact cellular compartment(s) in which this peptide is generated remain controversial. Nonetheless, it's been shown that Abeta can be generated within the endosomal/lysosomal compartment upon re-internalization of APP from the cell-surface. Our laboratory has previously demonstrated that the multi-ligand endocytic receptor LDL receptor-related protein (LRP) is capable of binding soluble APP and targeting it to the endosomal/lysosomal compartment for degradation. Recent studies suggest that LRP is also capable of binding full-length APP on the cell surface. The central hypothesis of this research proposal is that LRP plays a role in AD pathobiology by participating in the delivery of cell-surface APP to the endosomal/lysosomal compartment, which in turn favors generation of the Abeta peptide. This hypothesis will be addressed in the following specific aims: A. Determine if the treatment of cells with compounds that disrupt LRP-APP surface interaction results in decreased amyloidogenic processing of APP. B. Determine if removal of LRP will impair the amyloidogenic processing of APP.